To combat viral infection and evasion mechanisms, nature has implemented a multitude of partially overlapping defense strategies. The antiviral response is initiated through the recognition of viral products, such as double-stranded (ds) RNA, by three types of pathogen recognition receptors (PRRs) [1,2]:

the RIG-I-like receptors (RLRs),
the pro-apoptotic dsRNA sensors, and
the Toll-like receptors (TLRs).

Upon recognition of viral or synthetic dsRNA, these major PRRs mediate the transcriptional induction of proinflammatory cytokines, chemokines, and type I interferons (IFNs), thereby inducing hundreds of interferon-stimulated genes (ISGs). These products have antiviral, immunomodulatory, cell growth regulatory, and metabolic regulatory actions that create an antiviral state. If successful, this response potently restricts virus replication and cell-to-cell spread of infection [3].

MDA-5 & RIG-I

MDA-5 (Melanoma-differentiation-associated gene 5, IFIH1 or Helicard) and RIG-I (retinoic-acid-inducible protein 1, also known as Ddx58) are cytoplasmic RNA helicases belonging to the RLR family. Both sense dsRNA, a replication intermediate of RNA viruses, leading to the production of type I interferons (IFNs) [1]. They recognize a complementary set of cytosolic viral dsRNA [4]. MDA-5 recognizes long dsRNA and accordingly senses the single positive RNA viruses such as the poliovirus. On the contrary, RIG‐I prefers short dsRNA ligands and specifically recognizes most single‐negative RNA viruses which generate lots of short 5′ ppp‐dsRNA during replication (e.g. Influenza). Additionally, it can sense positive single RNA viruses such as the hepatitis C virus. It was also shown that RIG-I can detect certain DNA viruses and bacteria. Both RIG‐I and MDA-5 cross‐detect the same viruses, including rota and coronaviruses. The synthetic analog of viral dsRNA, transfected Poly(I:C), is also recognized by both sensors [4]. Upon viral infection, RIG-I and MDA5 are recruited by the adaptor protein MAVS (Mitochondrial antiviral-signaling protein) to the outer membrane of the mitochondria leading to the activation of several transcription factors including interferon-regulatory factor 3 (IRF3), IRF7, and NF-κB. Subsequently, IRFs and NF-κB regulate the expression of type I interferons (IFNs) and pro-inflammatory cytokines, respectively [1,5].

PKR

PKR (protein kinase R) is a member of the ISGs and plays a major role in central cellular processes such as mRNA translation, regulation of apoptosis, and cell proliferation [6]. It can respond to different stress situations including viral and bacterial dsRNA, pro-inflammatory factors, cytokines, mycotoxins, oxidative stress, and even miss-folded proteins [5-6]. In non-stressed cells, PKR exists in a monomeric, autoinhibitory state. Upon stressor (e.g. dsRNA) sensing, PKR triggers homodimerization by relieving its autoinhibitory form and undergoing rapid autophosphorylation. Once activated, PKR drives apoptosis by blocking mRNA translation. This suppression of general protein synthesis finally leads to the apoptosis of the infected cell and thus, limits viral replication [2, 6-7]. Interestingly, many viruses have developed mechanisms that prevent the establishment of an anti-viral state, by inhibiting components of the PKR pathway. These mechanisms include direct binding of PKR (thereby preventing autophosphorylation; e.g., Hepatitis C virus), changing its subcellular localization (e.g., Human and Murine Cytomegalovirus), or directing it for degradation (e.g., Rift valley fever virus) [6].

TLR3

Within the large family of TLRs, TLR3 is specialized in sensing viral-derived components and is mainly found in the endosome [8]. It recognizes mainly genomic dsRNA of reoviruses, as well as the intermediate RNAs generated during the replication of different viruses including herpes simplex virus‐1, and enteroviruses [3]. Its activation upon viral infection involves several steps, including translocation from the ER (endoplasmic reticulum) to the endosome, proteolytic cleavage and dimerization of TLR3, and finally receptor-ligand binding [9]. To start the signaling cascade, activated TLR3 recruits the adaptor protein TRIF (TIR domain-containing adapter-inducing interferon-β). TRIF binds to TRAF3 (TNF receptor-associated factor 3) and TRAF6, activating the transcription factor IRF3 and NF-κB, respectively. Ultimately, this leads to the production of type I IFNs (interferons) and pro-inflammatory cytokines [10-11].

References

1. Kawai T. et al., 2005. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol. 6(10):981-988.
2. Qiao, H, et al., 2021. Cell fate determined by the activation balance between PKR and SPHK1. Cell Death Differ 28, 401–418.
3. Kell AM, Gale M Jr., 2015. RIG-I in RNA virus recognition. Virology.;479-480:110-21.
4. Chen N, et al., 2017. RNA sensors of the innate immune system and their detection of pathogens. IUBMB Life.;69(5):297-304.
5. Pichlmair A. et al., 2006. RIG-I mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science 314:997-1001.
6. Gal-Ben-Ari S, et al. 2019. PKR: A Kinase to Remember. Front Mol Neurosci. ;11:480.
7. Dabo S, Meurs EF., 2012. dsRNA-dependent protein kinase PKR and its role in stress, signaling and HCV infection. Viruses. 4(11):2598-635.
8. Manuela Sironi, et al., 2012. A Common Polymorphism in TLR3 Confers Natural Resistance to HIV-1 Infection. J Immunol 15; 188 (2): 818–823.
9. Chen Y, et al., 2021. Toll-like receptor 3 (TLR3) regulation mechanisms and roles in antiviral innate immune responses. J Zhejiang Univ Sci B.;22(8):609-632.
10. Aluri, J, et al., 2021. Toll-Like Receptor Signaling in the Establishment and Function of the Immune System. Cells, 10, 1374.
11. Komal A, et al., 2021. TLR3 agonists: RGC100, ARNAX, and poly-IC: a comparative review. Immunol Res. 69(4):312-322.

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